PROJECT 1: DEVELOPING BIOMARKERS AND TREATMENTS FOR ASD AND ID IN TUBEROUS SCLEROSIS COMPLEX SUMMARY Current treatments for Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) can alleviate some symptoms but are limited in that none mechanistically target the underlying molecular basis for these conditions. Tuberous Sclerosis Complex (TSC) is a genetic disorder with high penetrance of ASD and ID. Inhibitors of the mechanistic target of rapamycin (mTOR) pathway are now approved for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), and epilepsy. To develop mTOR inhibitors and next-generation treatments for ASD and ID in TSC, there is critical need to better characterize the neurodevelopmental phenotype and to develop suitable biomarkers predictive of ASD/ID risk, severity, and treatment response. Using a prospective, longitudinal, multi-center design, we will (1) characterize the phenotype of ASD and ID in a large cohort of pediatric and adult patients with TSC in a prospective, multi-center longitudinal design; (2) identify electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and (3) evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically- meaningful outcomes in future ASD and ID clinical trials. Completion of these aims will provide mechanistic insight into the underlying pathological processes contributing to development of ASD and ID in TSC that can be targeted with mTOR inhibitors and next generation treatments in future clinical trials.